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Doukky et al. Cardiovascular Ultrasound 2014, 12:10 http://www.cardiovascularultrasound.com/content/12/1/10

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CARDIOVASCULAR ULTRASOUND

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The value of diastolic function parameters in the prediction of left atrial appendage thrombus in patients with nonvalvular atrial fibrillation Rami Doukky1,2*, Enrique Garcia-Sayan3, Heather Gage1, Vijaiganesh Nagarajan2, Anna Demopoulos1, Marek Cena2, Noreen T Nazir1, George J Karam1, Richard G Trohman1 and Rasa Kazlauskaite4

Abstract Background: Left ventricular diastolic impairment and consequently elevated filling pressure may contribute to stasis leading to left atrial appendage thrombus (LAAT) in nonvalvular atrial fibrillation (AF). We investigated whether transthoracic echocardiographic parameters can predict LAAT independent of traditional clinical predictors. Methods: We conducted a retrospective cohort study of 297 consecutive nonvalvular AF patients who underwent transthoracic echocardiogram followed by a transesophageal echocardiogram within one year. Multivariate logistic regression analysis models were used to determine factors independently associated with LAAT. Results: Nineteen subjects (6.4%) were demonstrated to have LAAT by transesophageal echocardiography. These patients had higher mean CHADS2 scores [2.6 ± 1.2 vs. 1.9 ± 1.3, P = 0.009], higher E:e’ ratios [16.6 ± 6.1 vs. 12.0 ± 5.4, P = 0.001], and lower mean e’ velocities [6.5 ± 2.1 cm/sec vs. 9.1 ± 3.2 cm/sec, P = 0.001]. Both E:e’ and e’ velocity were associated with LAAT formation independent of the CHADS2 score, warfarin therapy, left ventricular ejection fraction (LVEF), and left atrial volume index (LAVI) [E:e’ odds-ratio = 1.14 (95% confidence interval = 1.03 – 1.3), P = 0.009; e’ velocity odds-ratio = 0.68 (95% confidence interval = 0.5 – 0.9), P = 0.007]. Similarly, diastolic function parameters were independently associated with spontaneous echo contrast. Conclusion: The diastolic function indices E:e’ and e’ velocity are independently associated with LAAT in nonvalvular AF patients and may help identify patients at risk for LAAT. Keywords: Diastolic function, Left atrial appendage thrombus, Spontaneous echo contrast (SEC), Atrial fibrillation

Background Nonvalvular atrial fibrillation (AF) is the most common sustained cardiac dysrhythmia and the most frequent cause of cardio-embolic stroke [1]. It is well known that left atrial appendage thrombi (LAAT) are the source of most embolic strokes in patients with nonvalvular AF [2,3]. It is, likewise, widely accepted that transesophageal echocardiography (TEE) can identify LAAT and left atrial blood stasis, manifesting as spontaneous echo contrast (SEC), a known precursor of LAAT and systemic thromboembolism (Figure 1) [4-6]. * Correspondence: [email protected] 1 Division of Cardiology, Rush University Medical Center, 1653 W. Congress Pkwy, Chicago, IL 60612, USA 2 Division of Adult Cardiology, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA Full list of author information is available at the end of the article

It is physiologically plausible that impaired diastolic function and consequent elevation in the left ventricular filling pressure (LVFP) lead to left atrial stasis which results in LAAT formation and subsequent risk of systemic thromboembolism. Prior reports suggest that two-dimensional echocardiographic parameters such as left ventricular ejection fraction (LVEF), left atrial volume index (LAVI) and LVEF/LAVI are associated with LAAT in patients with AF [7,8]. In this investigation, we sought to determine whether e’ velocity (as a surrogate for left ventricular relaxation) and E:e’ (as a measure of left ventricular filling pressure) are predictive of LAAT formation and SEC independent of confounding covariates. Furthermore, we sought to integrate diastolic function indices with other echocardiographic

© 2014 Doukky et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.


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Figure 1 Representative examples. A: left atrial spontaneous echo contrast (SEC). B: left atrial appendage thrombus (arrow). C: Pulsed-wave Doppler recording of early diastolic mitral inflow velocity (E). D: Spectral tissue Doppler imaging of the lateral mitral annulus early diastolic velocity (e’).

parameters to propose a prediction rule for LAAT in patients with nonvalvular AF.

Methods Patient population and study design

A retrospective cohort study design was implemented. We queried the echocardiography laboratory database at Rush University Medical Center to identify all consecutive adult patients with nonvalvular AF who underwent a TEE to “rule-out” left atrial appendage thrombus between January 1, 2005 and December 31, 2009. Of those, we only included patients who had a previous transthoracic echocardiogram (TTE) within 1 year of the TEE. Patients with atrial flutter, without intervening episodes of atrial fibrillation, were not included. We excluded patients with valvular AF due to mitral stenosis and those with conditions known to alter E and e’ velocities; namely mitral regurgitation greater than 2+ in severity (on a 0 to 4 scale), post mitral valve surgical or percutaneous intervention, and post orthotopic heart transplantation status. Patients with isolated aortic valvular

disease, aortic valve prostheses and right-sided valvular heart disease were not excluded [1]. An expert board-certified (NBE) echocardiographer (RD), who was blinded to the TTE and clinical data, reviewed all TEE images to determine the presence or absence of LAAT [LAAT(+) and LAAT(−)], SEC and depressed left atrial appendage emptying velocity (0.18). E:e’ and e’ velocity association with LAAT

The mean E:e’ among LAAT(+) patients was significantly higher than those who were LAAT(−) [16.6 ± 6.1 vs. 12.0 ± 5.4, respectively; P = 0.001]. Conversely, the e’ velocity was significantly lower among LAAT(+) subjects [6.5 ± 2.1 vs. 9.1 ± 3.2, P = 0.006] (Figure 2, Table 2). Among LAAT(+) subjects, none (0%) had a normal E:e’ of ≤8; whereas 16 (84%) had an E:e’ ≥ 12, indicative of

elevated LVFP [18]. Furthermore, there was a stepwise increase in the prevalence of LAAT with increasing E:e’ and decreasing e’ velocity (Figure 3). Additionally, LAAT (+) subjects had a significantly higher LAVI and left ventricular volume index but lower LVEF (Table 2). Not surprisingly, there was a modest, but highly statistically significant, linear correlation between the CHADS2 score and diastolic indices of the E:e’ and e’ velocity, with Spearman’s correlation coefficients “r” of 0.34 (P < 0.001) and −0.32 (P < 0.001), respectively. Since only a minority of the patients (33%) were in sinus rhythm at the time of TTE, and thus had no A wave in the mitral inflow Doppler waveforms, it was not feasible to classify the patients based on their grade of diastolic dysfunction (typically graded from I to IV). A multivariate logistic regression analysis demonstrated that the CHADS2 score is associated with LAAT independent of warfarin use [OR = 1.47 per one point CHADS2 score increment (CI = 1.04-2.1), P = 0.03], while warfarin use had a borderline association with LAAT (Table 3; Model-1). When E:e’ was added to Model-1, it was independently associated with LAAT [OR = 1.14 per 1 point increment (CI = 1.05-1.2), P =0.002] and negated the effect of the CHADS2 score (Model-2, Table 3). To ensure that this association is not simply a confounder to impaired left ventricular function and left atrial volume, we added LVEF and LAVI to the model forming Model-3, in which E:e’, LVEF and LAVI were independently associated with LAAT, whereas the value of the CHADS2 and warfarin use was further negated (Table 3, Model-3). Similarly, when e’ velocity then LVEF and LAVI were sequentially introduced to Model-1 (Models 4 and 5), e’ velocity was independently “protective” of LAAT after adjusting for other covariates [OR = 0.68 for each 1 cm/sec increment in e’ velocity, P = 0.007] while the CHADS2 score was not (Table 3; Model-5). The Hosmer and Lemeshow test demonstrated a good fit of Models 3 and 5 (Table 3). Nearly identical results were obtained when analyzing the CHA2DS2-VASc score instead of CHADS2 score. Additionally, E:e’ and e’ velocity were also associated with LAAT independent of the individual components of CHADS2 score [E:e’ odds-ratio = 1.07 per 1 point increment (CI = 1.01-1.14), P = 0.02; e’ velocity odds-ratio = 0.87 per 1 cm/sec increment (CI = 0.77-0.98), P = 0.03]. These models maintained a good model fit (Hosmer and Lemeshow test P values = 0.30 and 0.23, respectively). Similar findings were noted with the CHA2DS2-VASc score. We did not test E:e’ and e’ velocity in a single regression model due to inherent co-linearity between these parameters. However, we compared (using ROC analysis) the diagnostic performance of the predicted probabilities of LAAT derived from an E:e’ based regression


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Figure 2 Box plots: E:e’ ratio and e’ velocity.

model (Model-3) versus an e’ velocity based one (Model-5). This analysis demonstrated that the contribution of E:e’ and e’ velocity to the prediction of LAAT was comparable, as the AUC associated with models 3 and 5 were similar (0.86 and 0.87, respectively; P = 0.33). E:e’ and e’ velocity association with SEC

One-hundred fourteen subjects (38%) had significant SEC by TEE, including all 19 subjects (100%) with LAAT (Table 2). These patients, as compared to those without SEC, had significantly higher mean E:e’ [14.2 (±5.6) vs. 11.4 (±5.4), P = 0.001] and lower e’ velocity [7.7 (±2.5) vs. 9.6 (±3.4) cm/sec, P < 0.001]. In multivariate logistic regression analyses, E:e’ and e’ velocity were associated with SEC independent of LVEF, LAVI, CHADS2 score, and warfarin therapy (Table 4), with similar results when substituting the CHA2DS2-VASc for the CHADS2 score. Diagnostic performance: ROC analyses

The receiver operator characteristics (ROC) curves demonstrated that the E:e’ and e’ velocity have good discriminatory capacity in predicting LAAT with respective areas under the curve (AUC) of 0.72 and 0.74, which trended to be larger than the 0.65 AUC associated with the CHADS2 score (P = 0.17 and 0.052, respectively), as shown in Figure 4. In this population, the ROC curve point-coordinates identified an E:e’ value of ≥9.4 to have 100% sensitivity and 38% specificity for LAAT; whereas E:e’ ≥ 15 was associated with a specificity of 78% at the

Table 2 Univariate analysis: Echocardiographic parameters LAAT (+)

LAAT (−)

P value

N = 19

N = 278

E:e’ ratio, mean ± SD

16.6 ± 6.1

12.0 ± 5.4

0.001

E:e’ > 8, n (%)

19 (100%)

195 (70%)

0.006

E:e’ ≥ 12, n (%)

16 (84%)

127 (46%)

0.001

e’ velocity (cm/sec), mean ± SD

6.5 ± 2.1

9.1 ± 3.2

0.001

Spontaneous echo contrast, n (%)

19 (100%)

95 (34%)

< 0.001

Depressed LAA emptying velocity*, n (%)

19 (100%)

132 (48.0%)

< 0.001

LA volume index (mL/m2), mean ± SD

44 ± 13

30 ± 13

< 0.001

LV volume index (mL/m2), mean ± SD

96 ± 38

73 ± 35

0.01

LV mass index (g/m2), mean ± SD

124 ± 45

124.0 ± 44

1.0

LVEF (%), mean ± SD

26 ± 17

45 ± 20

< 0.001

LAAT: left atrial appendage thrombus; SD: standard deviation; LAA: left atrial appendage; LA: left atrial; LV: left ventricular; LVEF: left ventricular ejection fraction. *LAA emptying velocity < 40 cm/sec.


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Figure 3 Prevalence of left atrial appendage thrombus based on E:e’ ratio and e’ velocity.

Table 3 Multivariate analysis: Predictors of left atrial appendage thrombus Odds-Ratio Clinical

Clinical, E/e’, and 2-D echo

95% CI

P value

Model 1 CHADS2 Score (per 1 point)

1.47

1.04 – 2.1

0.03

Warfarin

3.1

1.0 – 9.6

0.051

E/e’ (per 1 point)

1.14

1.05 – 1.2

0.002

CHADS2 score (per 1 point)

1.36

0.9 – 2.0

0.10

Warfarin

3.5

1.05 – 11.8

0.04

E/e’ (per 1 point)

1.14

1.03 – 1.3

0.009

LVEF (per 10 point)

0.62

0.4 – 0.9

0.008

LAVI (per 10 mL/m2)

1.59

1.1 – 2.3

0.02


0.93

0.6 – 1.5

0.74

Warfarin

2.73

0.7 – 10.7

0.15

e’ velocity (per 1 cm/sec)

0.70

0.6 – 0.9

0.004


1.27

0.9 – 1.8

0.20

Warfarin

2.87

0.9 – 9.5

0.08

e’ velocity (per 1 cm/sec)

0.68

0.5 – 0.9

0.007

LVEF (per 10 point)

0.67

0.5 – 1.01

0.03

LAVI (per 10 mL/m2)

1.89

1.3 – 2.8

0.002


0.86

0.5 – 1.4

0.53

Warfarin

2.1

0.6 – 7.9

0.26

Model-2

Model-3*

Clinical, e’ velocity, and 2-D echo

Model 4

Model 5*

2

CI: confidence intervals; LVEF: left ventricular ejection fraction (%); LAVI: left atrial volume index (mL/m ). *The Hosmer and Lemeshow test of the final models (3 and 5) showed good fit (P values = 0.91and 0.76, respectively).


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Table 4 Multivariate analysis: Predictors of spontaneous echo contrast Clinical

Clinical, E/e’, and 2-D echo

Clinical, e’ velocity, and 2-D Echo

Odds-Ratio

95% CI

P value

CHADS2 Score ( per 1 point)

1.39

1.2 – 1.7

0.001

Warfarin

2.22

1.4 – 3.7

0.002

E:e’ (per 1 point)

1.07

1.002 - 1.1

0.04

LVEF (per 10 point)

0.95

0.8 – 1.2

0.63

LAVI (per 10 mL/m2)

1.53

1.13 – 2.1

0.006

CHADS2 ( per 1 point)

1.22

0.9 – 1.6

0.20

Warfarin

2.06

1.01 – 4.2

0.048

0.85

0.7 – 0.97

0.01

1.0

0.8 – 1.2

0.98

Model-6

Model-7*

Model-8* e’ velocity (per

1 cm/sec)

LVEF (per 10 point) LAVI (per 10 mL/m2)

1.61

1.2 – 2.2

0.002

CHADS2 ( per 1 point)

1.18

0.9 – 1.6

0.29

Warfarin

1.94

0.94 – 4.0

0.07

CI: confidence intervals; LVEF: left ventricular ejection fraction (%); LAVI: left atrial volume index (mL/m2). *The Hosmer and Lemeshow test of the final models (7 and 8) showed good fit (P values = 0.25 and 0.75, respectively).

expense of a low sensitivity (32%). An e’ velocity ≤10 cm/sec was associated with 100% sensitivity for LAAT (Figure 4). Only a CHADS2 score of zero was “protective” from LAAT.

Discussion This retrospective cohort study of patients with nonvalvular AF demonstrates that the Doppler diastolic function parameters of E:e’ and e’ velocity are associated with LAAT formation and SEC independent of LVEF, LA volume, and other clinical predictors such as CHADS2 (or CHA2DS2-VASc) score and warfarin use. Furthermore, diastolic function parameters seem to negate the predictive value of the CHADS2 or CHA2DS2-VASc score. If prospectively validated, these findings would indicate that echocardiographic diastolic function parameters may help physicians identify patients at very low risk of LAAT, given their excellent sensitivity. Previous reports have demonstrated that reduced LVEF is associated with LAAT [7,19,20]. Despite the fact that E:e’ and e’ velocity are tightly related to systolic function, [18] we demonstrated that diastolic parameters are associated with LAAT independent of LVEF, likely driven by subjects with impaired diastolic function but preserved LVEF. Furthermore, the study findings are consistent with a recently published study by our group demonstrating that B-type Natriuretic Peptide, a surrogate for LVFP, is predictive of LAAT [21]. These findings are physiologically plausible, as atrial emptying is likely to be diminished with impaired diastolic relaxation and elevated LVFP, leading to atrial blood stasis and thrombus formation. This pathophysiology was the basis for the study hypothesis.

After the inception of this study Iwakura et al. reported that E:e’ is associated with LAAT independent of other echocardiographic parameters such as LVEF and LA dimensions [22]. Our investigation not only confirms these findings, but also demonstrates the independent association between diastolic function parameters and

Figure 4 Receiver operating characteristic curves. AUC: area under the curve; CI: confidence intervals. The receiver operating characteristic curves associated with the E:e’ ratio and CHADS2 score were not statistically different (P = 0.17); whereas the difference between the curves associated with e’ velocity and the CHADS2 score was borderline significant (P = 0.07).


LAAT beyond clinical and other echocardiographic risk predictors. A previous report has demonstrated that permanent AF is an independent predictor of LAAT, [23] a finding that was not confirmed in our study (Table 1). We suspect that permanent AF status is no more than a confounder for severe left ventricular systolic and diastolic impairment and left atrial enlargement. This study showed an association between warfarin use and LAAT (Model-1). Clearly, this is not a cause and effect relationship, but rather it is the result of a clinical bias as physicians are likely to use warfarin in patients perceived to be at high risk for LAAT and stroke. This association dissipated once we introduced diastolic parameters, LVEF and LAVI into the regression model. The authors are cognizant of the small sample size and infrequent LAAT events, which impaired our ability to analyze many covariates within a single regression model. Thus, we meticulously chose the covariates to be analyzed in the logistic regression models and we applied rigorous examination of the goodness of fit of all these models. Nevertheless, it is plausible that some weakly associated parameters may have been missed. Furthermore, the secondary SEC endpoint analyses were consistent with the primary endpoint analyses; thus adding validity to the study conclusions. Moreover, we chose not to test E:e’ and e’ velocity within a single regression model, as the inherent co-linearity between these indices is likely to negate the effects of one another. However, we demonstrated that the predictive values of regression models containing E:e’ and e’ velocity (Models 3 and 5) are similar. Our data does not demonstrate significant superiority of either parameter. LAVI was shown to be a strong independent predictor of LAAT in multiple reports; [7,8] a finding that was confirmed in this study. However, the predictive value of LAVI was greater when tested with e’ velocity (Model-5) vs. E:e’ (Model-3). This slight discrepancy is explained by the fact that left atrial enlargement is, in part, a manifestation of elevated LVFP assessed by E:e’ [18,24]. Thus, LAVI lost some of its predictive value after adjusting for E:e’. On the other hand, LAVI was a stronger predictor (OR = 1.89 per 10 mL/m2) when e’ velocity (rather than E:e’) was included in Model-5 (Table 3). This seems plausible since e’ velocity in itself is not a measure of LVFP. These findings further support the hypothesis that surrogate measures of LVFP such as LAVI, E:e’ or B-type natriuretic peptide are important predictors for LAAT. Predicting LAAT is certainly important in some clinical scenarios, such as prior to electrical cardioversion [25,26]. Since LAAT is the source of the majority of systemic thromboembolic events in patients with AF, [2,3] it is plausible that diastolic function parameters (E:e’ and

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e’ velocity) can also help predict embolic stroke. We speculate that, in nonvalvular AF, diastolic impairment and elevated LVFP represent the link between CHADS2 risk factors and systemic embolism [27]. We are fully aware that the patient population in this study is distinctly different from that of the AF patient population at large. Furthermore, although LAAT is a precursor of systemic thromboembolism and stroke, [28,29] these endpoints are not necessarily interchangeable. Further validation of this concept in a prospective hard endpoint (stroke) outcome study is warranted. Our study has a few limitations. First, the retrospective design is an obvious limitation. Second, although the majority of the TTEs were performed within a few days prior to the TEE, some preceded the TEE by as long as 12 months. Thus, the loading conditions at the time of the TTE and TEE may be different for many subjects. However, analysis of the relatively “volume independent” e’ velocity yielded similar results to those observed with E:e’, [30] supporting the study conclusions. Lastly, the small sample size and limited number of events constitute another limitation. Therefore, the findings of this hypothesis-generating study are not applicable clinically at this time, as they demand prospective validation.

Conclusion Our investigation demonstrates that the diastolic function indices of E:e’ and e’ velocity are associated with LAAT in patients with nonvalvular AF, independent of clinical and echocardiographic covariates. These findings need to be externally validated, and could potentially be incorporated into a prediction rule that could be utilized clinically for risk stratification for LAAT in patients with nonvalvular AF. Abbreviations AF: Atrial fibrillation; AUC: Area under the curve; CHF: Congestive heart failure; CI: Confidence intervals; E: Mitral inflow early-diastolic flow velocity; e’: Mitral annulus early-diastolic tissue velocity; INR: International normalized ratio; LA: Left atrial; LAAT: Left atrial appendage thrombus; LAVI: Left atrial volume index; LV: Left ventricular; LVEF: Ventricular ejection fraction; LVFP: Left ventricular filling pressure; OR: Odd-ratio; ROC: Receiver operating characteristic; SD: Standard deviation; SEC: Spontaneous echo contrast; TEE: Transesophageal echocardiography; TTE: Transesophageal echocardiogram. Competing interests The authors declare that they have no competing interests. Authors’ contributions RD, MD: Concept, design, statistical analysis, final manuscript approval. EG-S, MD: Echo image interpretation, manuscript drafting and editing. HG, MD: Echo image interpretation, design, manuscript drafting and editing. VN: data collection, cohort definition, data management, manuscript drafting and editing. AD, MD: data collection, data management, manuscript editing. MC, MD: data collection, data management, manuscript editing. NTN, MD: data collection, clinical adjudication. GJK, BS: data collection and management. RT, MD, MBA: critical review and editing. RK, MD, MSc: design, concept, critical review and editing. All authors read and approved the final manuscript.


Funding Rush-County Collaborative research grant (non-profit). Author details 1 Division of Cardiology, Rush University Medical Center, 1653 W. Congress Pkwy, Chicago, IL 60612, USA. 2Division of Adult Cardiology, John H. Stroger, Jr. Hospital of Cook County, Chicago, IL, USA. 3Division of Cardiology, Mount Sinai Hospital, Chicago, IL, USA. 4Department of Preventive Medicine, Rush University Medical Center, Chicago, IL, USA. Received: 13 January 2014 Accepted: 17 February 2014 Published: 25 February 2014

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